Rituximab or Splenectomy in Steroid-Resistant ITP Patients?

Sunday, March 1, 2015

Corticosteroids are the standard initial treatment for adult patients with idiopathic thrombocytopenic purpura (ITP), while splenectomy is considered second-line treatment. Drugs like rituximab have led to a trend in delaying or avoiding splenectomy.

Should splenectomy remain an early intervention, or should clinicians exhaust all available medical treatment options before performing this irreversible procedure?

ASH Clinical News has invited Craig Kitchens, MD, and Keith McCrae, MD, to debate the question: “For ITP, should splenectomy or rituximab be used as first-line therapy after steroids?” Dr. Kitchens will be arguing for splenectomy, and Dr. McCrae will be arguing for rituximab.

Craig S. Kitchens, MD: Before we start debating the question of which therapeutic approach is best for these patients, I think we have to acknowledge that we are very lucky to have a choice – for once – of effective second-line therapies for our ITP patients. With some other platelet disorders, like thrombotic thrombocytopenia purpura (TTP), the second- or third-line therapeutic options are not as effective. We don’t have the luxury there of asking, “Which of these two options is better?” We have to ask, “Which is the least bad?”

Regarding our current topic, though, each of these options – rituximab or splenectomy – is effective and rather safe, but I would say that there are definite differences in long-term efficacy, with the advantage going to splenectomy.

I do use rituximab, and I’m sure that you recommend a splenectomy every now and then.

Keith McCrae, MD: I’d agree with you that we are in a privileged position. When I am treating adult patients with ITP there are certain situations when I would opt for splenectomy. However, I choose rituximab first for a few straightforward reasons: it is quite effective, it is well-tolerated, and it does offer the possibility for a durable remission of ITP. Also, many of my patients simply do not want splenectomies.

In addition, I am concerned about the emerging literature that has found that there are, indeed, long-term consequences of splenectomy that may not have been fully appreciated. That is another issue that weighs on my decision to reach for rituximab first in patients with steroid-resistant ITP.

Dr. Kitchens: I’ve been practicing hematology for a while, so I have seen a lot of growth in this area. For a while, I was known among my colleagues as a “defender of the spleen.” Nobody’s spleen was coming out on my watch!

We would give patients all kinds of medication – none of which were as effective as rituximab – or we would administer vinblastine-loaded platelets. The problem with those approaches were the response rates – only about 20 percent of patients responded. We thought that was just the natural course of the disease in certain patients. A small percentage of patients who had maintained a platelet count of 60,000 would even come to clinic and, all of a sudden, would reach a platelet count of 320,000.

On top of that, I had seen several patients who underwent splenectomy with drastic and occasionally fatal post-splenectomy infections.
So, why did I switch from the “defender of the spleen” to favoring splenectomy in most situations? Well, I have to say that I haven’t totally abandoned other options. Frankly, I don’t want to; there is just too much going on in ITP.

But, I have learned a lot of durable lessons from my patients. Two unique cases come to mind, both of whom had ITP that would intermittently respond to prednisone. Both were also missionaries preparing to go to remote places in Rwanda and Haiti, respectively, where they would be pretty isolated from care. The last thing they wanted was to have a relapse of their ITP, or to find themselves in a situation where they needed a blood transfusion while there. Since we aren’t able to check the patient’s platelet count or dose-adjust the medication for an extended period of time, we needed something durable. So, we decided to go with splenectomy for both of these patients and they both did very well for the years they were out of range of immediate care.

Obviously, those are two very specific cases, but they highlight one of the major reasons for choosing splenectomy as second-line therapy: the durability and ability to go for longer periods without treatment.

Dr. McCrae: You make a good point, Dr. Kitchens. There are some younger adult patients – missionaries or not – who say to me, “Look, I don’t want to come to the doctor’s office. I’m in a far, distant land – it’s called college – and I never want to see the doctor.” For certain patients, that is their main concern; they don’t want to worry about their platelet count in their day-to-day life and they want the most definitive long-term treatment, which is splenectomy. I don’t try to talk them out of it, but I just make sure that I present the options. If for some reason I feel that one option is better than another, I’ll push them in that direction.

The point I always make when I discuss management of ITP is that every patient is different; you have to individualize the therapy to the patient. We operate in an era of guidelines and flowcharts outlining how to treat patients if they meet certain criteria. That may work well for certain diseases – particularly for oncologic diseases, where there is an abundance of data from randomized controlled trials – but ITP is a rare condition. We are lacking head-to-head comparisons of these different therapeutic approaches. That’s why individualization is so critical.

Dr. Kitchens: Absolutely. And honestly, I believe that the mortality of ITP and the incidence of fatal bleeding from ITP is much lower than nearly all physicians estimate. I realized this in my own practice over the past two decades; very few deaths occurred, and only in very complex cases. This was supported in the literature: James N. George, MD, and colleagues found that the overall mortality of ITP is less than 5 percent, and operative mortality with splenectomy was less than 1 percent.1,2 Furthermore, 66 percent of the 2,623 patients with one- to 153-month follow up experienced a complete response, and relapse rates were only a median of 15 percent.

Dr. McCrae: There are some interesting data that I think are closing the gap between rituximab and splenectomy in terms of which approach offers the best, most durable response. Newer studies are showing that there are long-term responses with rituximab. Last year, James B. Bussel, MD, and colleagues published results of upfront treatment with rituximab plus three cycles of dexamethasone in patients who had ITP for less than two years.3 After more than five years of follow-up, about two-thirds of patients experienced long-term responses, which is comparable to response rates with splenectomy.

Risk of infection is another area in which rituximab may have an advantage. Clearly, the overall risk of infection is higher in splenectomized patients, but the literature on rates of infection in rituximab-treated patients is more controversial. It depends on whether a patient is vaccinated prior to receiving rituximab; this may be more commonly done in Europe, but I try to vaccinate most patients in my practice who plan to start rituximab. Occasionally, patients do not respond well to rituximab and need a splenectomy quickly, so immunization of such patients after receiving rituximab is not optimal.

Infection, though uncommon after splenectomy, is definitely a concern, and will remain a concern. Patients undergoing splenectomy may need prophylactic antibiotics and need proper education about the risk of infection.

We’ve mentioned patient preference – but what about cost? Looking at rituximab, the cost, to my knowledge, is about $20,000, though that depends largely upon institutional agreements. I suspect splenectomy is considerably more expensive in most hospitals.

Dr. Kitchens: On the splenectomy side, cost depends on the approach – with laparoscopic splenectomy, there will be a decrease in morbidity and mortality which, as has been shown in meta-analyses, is already very low. In my experience, though, there is not a great savings with the laparoscopic splenectomy, as opposed to the open surgical approach.

Another issue I hear from many hematologists whom I have trained is, in determining whether a patient even needs therapy, how low is too low in terms of platelet counts? Is a count of 45,000 platelets low enough to start rituximab or to undergo splenectomy? In my opinion, that patient doesn’t need anything with those types of numbers. This feeds into the idea of the hematologist as the ultimate “therapeutic nihilist,” but I would not subject any patient to either of those treatments if their platelet counts were in a safe range – especially now that we have thrombopoietin-receptor agonists like eltrombopag and romiplostim.

In my 40 years of doing this, there has been approximately every variable you can possibly imagine for deciding treatment – gender, age, whether the patient has lupus – but none of these variables has a major impact on outcomes.

Dr. McCrae: The only factor that may have some value is age – younger patients respond better to treatment than older patients. But I agree that there are many potential predictors of response that may be helpful on a population basis, but not on an individual patient basis. So, I don’t think we can rely on any of those factors for choosing one treatment approach over the other.

Overall, I would say the quality of life for corticosteroid-resistant ITP patients is comparable after receiving rituximab or undergoing splenectomy. Sure, it’s a bother to have to come in for weekly rituximab infusions for four weeks, but it is still no more of a burden than having to undergo surgery – even if the procedure is done laparoscopically. This is particularly true if the patient turns out to be a splenectomy non-responder.

Dr. Kitchens: Exactly; a patient’s unique situation is more important than following a treatment algorithm. There is no guideline that will capture every single case.

Dr. McCrae: Medical treatment of ITP is still somewhat of a moving target, and there are some new and innovative approaches being suggested, even with rituximab. Whenever you debate what is best for patients, you have to remember that guidelines apply more or less to populations – they don’t always apply to every individual.

References

George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3-40.

Bussel JB, Lee CS, Seery C, et al. Rituximab and three dexamethasone cycles provide responses similar to splenectomy in women and those with immune thrombocytopenia of less than two years duration. Haemotologica. 2014;99:1264-71.